Obesity has become a national epidemic. The health consequences are manifold including increases in the risk and prevalence of metabolic syndrome (MetS) and non- alcoholic fatty liver disease (NAFLD). The metabolic underpinnings of these conditions, both of which are influenced by obesity and, specifically, increased stores of abdominal visceral fat and insulin resistance, are highly intertwined and have both genetic and environmental determinants. Characterization of fatty liver (steatosis) in conjunction with liver enzymes and abdominal fat depots in a large family study will provide an unprecedented opportunity to study the genetic epidemiology of MetS and NAFLD. Using existing CT scans obtained in over 3,300 Caucasian and African-American subjects from families of the NHLBI Family Heart Study (FHS), we propose to obtain measures of four focal phenotypes: liver attenuation, and total, subcutaneous, and visceral abdominal fat. Combined with the wealth of phenotypic and genetic information available already in the FHS, we will carry out studies of the genetic epidemiology of these important phenotypes, with the goal of identifying risk factors for these diseases including both genetic and environmental factors. We will use standard epidemiological models to characterize the risk factors for NAFLD, specifically, dietary factors (as ascertained using the Willett questionnaire), habitual physical activity, and alcohol consumption. Using existing measures of coronary and aortic artery calcification on these subjects, we will also characterize the influence of steatosis and abdominal fat on the degree of subclinical atherosclerosis. While the genetic basis of abdominal fat is well-established exhibiting a heritability of 50-70%, a recent study has estimated the heritability of liver attenuation to be 34%, suggesting that mapping studies are warranted. Genetic scans will be carried out in both Caucasian and African-American families using a panel of over 400 microsatellite linkage markers that are already typed on these subjects, to identify regions harboring trait loci. Genomewide association scans are being currently conducted for 1,000 Caucasian cases and controls for atherosclerosis, and for all 622 African-American subjects. These genotypes also will be available to this project to enhance the power for gene discovery and localization. Finally, we are particularly interested in characterizing the systems biological multivariate relationships among our focal phenotypes with other aspects of the MetS including insulin and glucose levels, insulin resistance, blood pressure, and lipids and lipoproteins in order to identify determinants that explain the clustering in this adverse risk factor profile. The proposed studies will help localize genes involved in the metabolic diseases of obesity, help elucidate the role of environmental exposures in these pathways, and will be among the largest, most definitive studies to date on fatty liver disease. Obesity has become a national epidemic. The health consequences are manifold including increases in the risk and prevalence of diabetes, metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD). The metabolic underpinnings of these conditions, all of which are influenced and exacerbated by obesity are highly intertwined and have both genetic and environmental determinants. The overall goal of this project is to study abdominal fat patterning and NAFLD, both of which are associated with insulin resistance, to identify their underlying genetic architecture using state of the art genome screening methods, evaluate the influence of diet and physical activity, and to understand their relationship to features of the MetS and coronary artery disease. PUBLIC HEALTH RELEVANCE: Obesity has become a national epidemic. The health consequences are manifold including increases in the risk and prevalence of diabetes, metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD). The metabolic underpinnings of these conditions, all of which are influenced and exacerbated by obesity are highly intertwined and have both genetic and environmental determinants. The overall goal of this project is to study abdominal fat patterning and NAFLD, both of which are associated with insulin resistance, to identify their underlying genetic architecture using state of the art genome screening methods, evaluate the influence of diet and physical activity, and to understand their relationship to features of the MetS and coronary artery disease.